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1.
Jesse Rowley Archana Monie Chien‐Fu Hung T.‐C. Wu 《European journal of immunology》2009,39(2):491-506
IL‐15 and IL‐15 receptor alpha (IL‐15RA) play a significant role in multiple aspects of T‐cell biology. However, given the evidence that IL‐15RA can present IL‐15 in trans, the functional capacity of IL‐15RA expressed on CD8+ T cells to modify IL‐15 functions in cis is currently unclear. In the current study, we explore the functional consequences of IL‐15RA, expression on T cells using a novel method to transfect naive CD8+ T cells. We observed that RNA nucleofection led to highly efficient, non‐toxic, and rapid manipulation of protein expression levels in unstimulated CD8+ T cells. We found that transfection of unstimulated CD8+ T cells with IL‐15RA RNA led to enhanced viability of CD8+ T cells in response to IL‐15. Transfection with IL‐15RA enhanced IL‐15‐mediated phosphorylation of STAT5 and also promoted IL‐15‐mediated proliferation in vivo of adoptively transferred naïve CD8+ T cells. We demonstrated that IL‐15RA can present IL‐15 via cis‐presentation on CD8+ T cells. Finally, we showed that transfection with a chimeric construct linking IL‐15 to IL‐15RA cell autonomously enhances the viability and proliferation of primary CD8+ T cells and cytotoxic potential of antigen‐specific CD8+ T cells. The clinical implications of the current study are discussed. 相似文献
2.
A. Di Stefano G. Caramori I. Gnemmi M. Contoli C. Vicari A. Capelli F. Magno S. E. D'Anna A. Zanini P. Brun P. Casolari K. F. Chung P. J. Barnes A. Papi I. Adcock B. Balbi 《Clinical and experimental immunology》2009,157(2):316-324
There are increased numbers of activated T lymphocytes in the bronchial mucosa of stable chronic obstructive pulmonary disease (COPD) patients. T helper type 17 (Th17) cells release interleukin (IL)‐17 as their effector cytokine under the control of IL‐22 and IL‐23. Furthermore, Th17 numbers are increased in some chronic inflammatory conditions. To investigate the expression of interleukin (IL)‐17A, IL‐17F, IL‐21, IL‐22 and IL‐23 and of retinoic orphan receptor RORC2, a marker of Th17 cells, in bronchial biopsies from patients with stable COPD of different severity compared with age‐matched control subjects. The expression of IL‐17A, IL‐17F, IL‐21, IL‐22, IL‐23 and RORC2 was measured in the bronchial mucosa using immunohistochemistry and/or quantitative polymerase chain reaction. The number of IL‐22+ and IL‐23+ immunoreactive cells is increased in the bronchial epithelium of stable COPD compared with control groups. In addition, the number of IL‐17A+ and IL‐22+ immunoreactive cells is increased in the bronchial submucosa of stable COPD compared with control non‐smokers. In all smokers, with and without disease, and in patients with COPD alone, the number of IL‐22+ cells correlated significantly with the number of both CD4+ and CD8+ cells in the bronchial mucosa. RORC2 mRNA expression in the bronchial mucosa was not significantly different between smokers with normal lung function and COPD. Further, we report that endothelial cells express high levels of IL‐17A and IL‐22. Increased expression of the Th17‐related cytokines IL‐17A, IL‐22 and IL‐23 in COPD patients may reflect their involvement, and that of specific IL‐17‐producing cells, in driving the chronic inflammation seen in COPD. 相似文献
3.
This study is designed to investigate the changes of NKG2D expression on CD8+T cells and CD3?CD56+NK cells in Kawasaki disease (KD). NKG2D/NKG2A expression on CD3?CD56+NK cells and CD8+T lymphocytes, and NKG2D ligands such as major histocompatibility complex I chain‐related molecules A(MICA) and UL‐16‐binding proteins (ULBP‐1) expression on CD14+ mononuclear cells (MC) were analysed by flow cytometry in patients with KD. Real‐time polymerase chain reaction (PCR) was used to evaluate the mRNA levels of interleukin (IL)‐1β, IL‐6 and tumour necrosis factor (TNF)‐α in CD14+ cells. Plasma cytokine [IL‐7, IL‐12, IL‐15, interferon (IFN)‐γ and transforming growth factor (TGF)‐β] concentrations were measured by ELISA. The levels of NKG2D on NK cells and CD8+T cells expression in acute phase of KD were significantly lower than those in normal controls (P < 0.05), and the levels of NKG2D expression in the patients with coronary artery lesion (KD‐CAL+) were lower than those in patients with KD‐CAL?. There was an upregulated tendency after treatment with IVIG. We found higher expression levels of proinflammatory cytokines from MC, such as IL‐1β, IL‐6 and TNF‐α in patients with KD compared with the healthy controls (P < 0.05). The concentrations of IL‐7 and IL‐15 were significantly decreased in acute phase of KD (P < 0.05) and to some extent elevated after therapy with IVIG (P < 0.05), while antagonistic cytokines like IFN‐γ were increased in acute phase of KD (P < 0.05) and reduced after therapy with IVIG (P < 0.05). These results suggest that aberrantly decreased levels of NKG2D expression on NK cells and CD8+T cells might be one of the factors led to disturbed immunological function in patients with KD. Cytokines milieu could be important factors causing reduced expression of NKG2D. 相似文献
4.
Angela M. Crawley Agatha Vranjkovic Charlene Young Jonathan B. Angel 《European journal of immunology》2010,40(5):1396-1407
Signaling via the IL‐7 receptor complex (IL‐7Rα/CD127 and IL‐2Rγ/CD132) is required for T‐cell development and survival. Decreased CD127 expression has been associated with persistent viral infections (e.g. HIV, HCV) and cancer. Many IL‐2Rγ‐sharing (γC) cytokines decrease CD127 expression on CD4+ and CD8+ T cells in mice (IL‐2, IL‐4, IL‐7, IL‐15) and in humans (IL‐2, IL‐7), suggesting a common function. IL‐4 is of particular interest as it is upregulated in HIV infection and in thyroid and colon cancers. The role of IL‐4 in regulating CD127 expression and IL‐7 activity in human thymocytes and mature CD8+ T cells is unknown and was therefore investigated. IL‐4 decreased CD127 expression on all thymocyte subsets tested and only on naïve (CD45RA+) CD8+ T cells, without altering membrane‐bound CD127 mRNA expression. Pre‐treatment of thymocytes or CD8+ T cells with IL‐4 inhibited IL‐7‐mediated phosphorylation of STAT5 and decreased proliferation of CD8+ T cells. By downregulating CD127 expression and signaling on developing thymocytes and CD8+ T cells, IL‐4 is a potential contributor to impaired CD8+ T‐cell function in some anti‐viral and anti‐tumor responses. These findings are of particular consequence to diseases such as HIV, HCV, RSV, measles and cancer, in which CD127 expression is decreased, IL‐7 activity is impaired and IL‐4 concentrations are elevated. 相似文献
5.
IL‐15 is a pleiotropic cytokine involved in host defense as well as autoimmunity. IL‐15‐deficient mice show a decrease of memory phenotype (MP) CD8+ T cells, which develop naturally in naïve mice and whose origin is unclear. It has been shown that self‐specific CD8+ T cells developed in male H‐Y antigen‐specific TCR transgenic mice share many similarities with naturally occurring MP CD8+ T cells in normal mice. In this study, we found that H‐Y antigen‐specific CD8+ T cells in male but not female mice decreased when they were crossed with IL‐15‐deficient mice, mainly due to impaired peripheral maintenance. The self‐specific TCR transgenic CD8+ T cells developed in IL‐15‐deficient mice showed altered surface phenotypes and reduced effector functions ex vivo. Bystander activation of the self‐specific CD8+ T cells was induced in vivo during infection with Listeria monocytogenes, in which proliferation but not IFN‐γ production was IL‐15‐dependent. These results indicated important roles for IL‐15 in the maintenance and functions of self‐specific CD8+ T cells, which may be included in the naturally occurring MP CD8+ T‐cell population in naïve normal mice and participate in innate host defense responses. 相似文献
6.
TRAF2 regulates peripheral CD8+ T‐cell and NKT‐cell homeostasis by modulating sensitivity to IL‐15
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Jeanette E. Villanueva Elisabeth K. Malle Sandra Gardam Pablo A. Silveira Nathan W. Zammit Stacey N. Walters Robert Brink Shane T. Grey 《European journal of immunology》2015,45(6):1820-1831
In this study, a critical and novel role for TNF receptor (TNFR) associated factor 2 (TRAF2) is elucidated for peripheral CD8+ T‐cell and NKT‐cell homeostasis. Mice deficient in TRAF2 only in their T cells (TRAF2TKO) show ∼40% reduction in effector memory and ∼50% reduction in naïve CD8+ T‐cell subsets. IL‐15‐dependent populations were reduced further, as TRAF2TKO mice displayed a marked ∼70% reduction in central memory CD8+CD44hiCD122+ T cells and ∼80% decrease in NKT cells. TRAF2TKO CD8+CD44hi T cells exhibited impaired dose‐dependent proliferation to exogenous IL‐15. In contrast, TRAF2TKO CD8+ T cells proliferated normally to anti‐CD3 and TRAF2TKO CD8+CD44hi T cells exhibited normal proliferation to exogenous IL‐2. TRAF2TKO CD8+ T cells expressed normal levels of IL‐15‐associated receptors and possessed functional IL‐15‐mediated STAT5 phosphorylation, however TRAF2 deletion caused increased AKT activation. Loss of CD8+CD44hiCD122+ and NKT cells was mechanistically linked to an inability to respond to IL‐15. The reduced CD8+CD44hiCD122+ T‐cell and NKT‐cell populations in TRAF2TKO mice were rescued in the presence of high dose IL‐15 by IL‐15/IL‐15Rα complex administration. These studies demonstrate a critical role for TRAF2 in the maintenance of peripheral CD8+ CD44hiCD122+ T‐cell and NKT‐cell homeostasis by modulating sensitivity to T‐cell intrinsic growth factors such as IL‐15. 相似文献
7.
8.
IL‐12 and IL‐4 activate a CD39‐dependent intrinsic peripheral tolerance mechanism in CD8+ T cells
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Alistair Noble Hema Mehta Andrew Lovell Eleftheria Papaioannou Lynette Fairbanks 《European journal of immunology》2016,46(6):1438-1448
Immune responses to protein antigens involve CD4+ and CD8+ T cells, which follow distinct programs of differentiation. Naïve CD8 T cells rapidly develop cytotoxic T‐cell (CTL) activity after T‐cell receptor stimulation, and we have previously shown that this is accompanied by suppressive activity in the presence of specific cytokines, i.e. IL‐12 and IL‐4. Cytokine‐induced CD8+ regulatory T (Treg) cells are one of several Treg‐cell phenotypes and are Foxp3? IL‐10+ with contact‐dependent suppressive capacity. Here, we show they also express high level CD39, an ecto‐nucleotidase that degrades extracellular ATP, and this contributes to their suppressive activity. CD39 expression was found to be upregulated on CD8+ T cells during peripheral tolerance induction in vivo, accompanied by release of IL‐12 and IL‐10. CD39 was also upregulated during respiratory tolerance induction to inhaled allergen and on tumor‐infiltrating CD8+ T cells. Production of IL‐10 and expression of CD39 by CD8+ T cells was independently regulated, being respectively blocked by extracellular ATP and enhanced by an A2A adenosine receptor agonist. Our results suggest that any CTL can develop suppressive activity when exposed to specific cytokines in the absence of alarmins. Thus negative feedback controls CTL expansion under regulation from both nucleotide and cytokine environment within tissues. 相似文献
9.
10.
Inflammatory cell profiles and T-lymphocyte subsets in chronic obstructive pulmonary disease and severe persistent asthma 总被引:3,自引:0,他引:3
M. Tsoumakidou N. Tzanakis D. Kyriakou G. Chrysofakis N. M. Siafakas 《Clinical and experimental allergy》2004,34(2):234-240
Background Severe persistent asthma (SPA) and chronic obstructive pulmonary disease (COPD) are both associated with non‐reversible airflow limitation and airway neutrophilia. Objective To compare inflammatory cell profiles and T lymphocyte subsets between SPA and COPD patients with similar severity of airflow limitation. Methods Sputum induction and lung function tests were performed in 15 COPD patients aged (mean±SD) 68±8 years, ex‐smokers, mean forced expiratory volume in 1 s (FEV1) 45% of predicted (%pred) and 13 SPA aged 55±10 years, non‐smokers, mean FEV1 49%pred. All patients were on inhaled steroid treatment. Eight asthmatics exhibited irreversible airflow limitation. Differential cell count, metachromatic cell count and double immunocytochemistry for the analysis of T lymphocyte subsets were performed on sputum slides. Results COPD patients had increased sputum neutrophils in comparison with SPA (P<0.03), but similar to SPA with fixed obstruction. In COPD sputum neutrophils negatively correlated with the lung transfer factor for carbon monoxide (KCO) (r=?0.462, P=0.04). SPA showed significantly increased eosinophils and metachromatic cells vs. COPD patients (P<0.04, P<0.007, respectively). Increased CD4/CD8 and decreased CD4‐IFN‐γ/CD4‐IL4+ cell ratio (P<0.001) were found in SPA vs. COPD. In SPA, CD4/CD8+ cell ratio correlated with sputum eosinophils (r=0.567, P=0.04). Conclusion In spite of treatment with inhaled steroids, SPA and COPD exhibit distinct sputum inflammatory cell patterns, although SPA with fixed airflow limitation and COPD patients have similar numbers of neutrophils. 相似文献
11.
Stefano Caserta Patrizia Alessi Veronica Basso Anna Mondino 《European journal of immunology》2010,40(2):470-479
It is well established that tumours hinder both natural and vaccine‐induced tumour‐specific CD4+ T‐cell responses. Adoptive T‐cell therapy has the potential to circumvent functional tolerance and enhance anti‐tumour protective responses. While protocols suitable for the expansion of cytotoxic CD8+ T cells are currently available, data on tumour‐specific CD4+ T cells remain scarce. We report here that CD4+ T cells sensitized to tumour‐associated Ag in vivo, proliferate in vitro in response to IL‐7 without the need for exogenous Ag stimulation and accumulate several folds while preserving a memory‐like phenotype. Both cell proliferation and survival accounts for the outgrowth of tumour‐sensitized T cells among other memory and naive lymphocytes following exposure to IL‐7. Also IL‐2, previously used to expand anti‐tumour CTL, promotes tumour‐specific CD4+ T‐cell accumulation. However, IL‐7 is superior to IL‐2 at preserving lymphocyte viability, in vitro and in vivo, maintaining those properties, that are required by helper CD4+ T cells to confer therapeutic efficacy upon transplantation in tumour‐bearing hosts. Together our data support a unique role for IL‐7 in retrieving memory‐like CD4+ T cells suitable for adoptive T‐cell therapy. 相似文献
12.
L. S. Harbige E. Pinto J. Allgrove L. V. Thomas 《Scandinavian journal of immunology》2016,84(6):353-364
Daily ingestion of a probiotic drink containing Lactobacillus casei Shirota (LcS; 1.3 × 1010 live cells) by healthy adults for (1) 4‐week LcS, (2) 6‐week discontinuation of LcS and (3) a final 4 weeks of LcS was investigated. There was a significant increase in expression of the T cell activation marker CD3+CD69+ in ex vivo unstimulated blood cells at weeks 10 and 14, and there was a significant increase in the NK cell marker CD3+CD16/56+ in ex vivo unstimulated blood cells at weeks 4, 10 and 14. Expression of the NK cell activation marker CD16/56+CD69+ in ex vivo unstimulated blood cells was 62% higher at week 10 and 74% higher at week 14. Intracellular staining of IL‐4 in ex vivo unstimulated and PMA‐/ionomycin‐stimulated CD3+ β7+ integrin blood cells was significantly lower at weeks 10 and 14. Intracellular staining of IL‐12 in ex vivo unstimulated and LPS‐stimulated CD14+ blood cells was significantly lower at weeks 4, 10 and 14. Intracellular staining of TNF‐α in LPS‐stimulated CD14+ blood cells was significantly lower at weeks 4, 10 and 14. Mucosal salivary IFN‐γ, IgA1 and IgA2 concentrations were significantly higher at week 14, but LcS did not affect systemic circulating influenza A‐specific IgA or IgG and tetanus‐specific IgG antibody levels. In addition to the decrease in CD3+β7+ integrin cell IL‐4 and a reduced CD14+ cell pro‐inflammatory cytokine profile, at week 14 increased expression of activation markers on circulating T cells and NK cells and higher mucosal salivary IgA1 and IgA2 concentration indicated a secondary boosting effect of LcS. 相似文献
13.
CD161++CD8+ T cells,including the MAIT cell subset,are specifically activated by IL‐12+IL‐18 in a TCR‐independent manner
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James E. Ussher Matthew Bilton Emma Attwod Jonathan Shadwell Rachel Richardson Catherine de Lara Elisabeth Mettke Ayako Kurioka Ted H. Hansen Paul Klenerman Christian B. Willberg 《European journal of immunology》2014,44(1):195-203
CD161++CD8+ T cells represent a novel subset that is dominated in adult peripheral blood by mucosal‐associated invariant T (MAIT) cells, as defined by the expression of a variable‐α chain 7.2 (Vα7.2)‐Jα33 TCR, and IL‐18Rα. Stimulation with IL‐18+IL‐12 is known to induce IFN‐γ by both NK cells and, to a more limited extent, T cells. Here, we show the CD161++ CD8+ T‐cell population is the primary T‐cell population triggered by this mechanism. Both CD161++Vα7.2+ and CD161++Vα7.2? T‐cell subsets responded to IL‐12+IL‐18 stimulation, demonstrating this response was not restricted to the MAIT cells, but to the CD161++ phenotype. Bacteria and TLR agonists also indirectly triggered IFN‐γ expression via IL‐12 and IL‐18. These data show that CD161++ T cells are the predominant T‐cell population that responds directly to IL‐12+IL‐18 stimulation. Furthermore, our findings broaden the potential role of MAIT cells beyond bacterial responsiveness to potentially include viral infections and other inflammatory stimuli. 相似文献
14.
15.
IL‐15‐dependent CD8+CD122+ T cells ameliorate experimental autoimmune encephalomyelitis by modulating IL‐17 production by CD4+ T cells
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Interleukin‐15 (IL‐15) is an inflammatory cytokine whose role in autoimmune diseases has not been fully elucidated. Th17 cells have been shown to play critical roles in experimental autoimmune encephalomyelitis (EAE) models. In this study, we demonstrate that blockade of IL‐15 signaling by TMβ‐1 mAb treatment aggravated EAE severity. The key mechanism was not NK‐cell depletion but depletion of CD8+CD122+ T cells. Adoptive transfer of exogenous CD8+CD122+ T cells to TMβ‐1‐treated mice rescued animals from severe disease. Moreover, transfer of preactivated CD8+CD122+ T cells prevented EAE development and significantly reduced IL‐17 secretion. Naïve effector CD4+CD25? T cells cultured with either CD8+CD122+ T cells from wild‐type mice or IL‐15 transgenic mice displayed lower frequencies of IL‐17A production with lower amounts of IL‐17 in the supernatants when compared with production by effector CD4+CD25? T cells cultured alone. Addition of a neutralizing antibody to IL‐10 led to recovery of IL‐17A production in Th17 cultures. Furthermore, coculture of CD8+CD122+ T cells with effector CD4+ T cells inhibited their proliferation significantly, suggesting a regulatory function for IL‐15 dependent CD8+CD122+ T cells. Taken together, these observations suggest that IL‐15, acting through CD8+CD122+ T cells, has a negative regulatory role in reducing IL‐17 production and Th17‐mediated EAE inflammation. 相似文献
16.
LPS comprises a major PAMP and is a key target of the immune system during bacterial infection. While LPS can be recognised by innate immune cells via the TLR4 complex, it is unknown whether T lymphocytes, especially CD8+ T cells are also capable of doing so. We report here that naïve human CD8+ T cells, after activation by TCR stimulation, express surface TLR4 and CD14. These activated CD8+ T cells can then secrete high concentrations of IFN‐γ, granzyme and perforin in response to LPS. These effects can be specifically inhibited using siRNA for TLR4. Furthermore, LPS can synergise with IL‐12 to polarise the CD8+ T cells into cytotoxic T‐cell 1 (Tc1) that produce IFN‐γ but not IL‐4, with or without TCR activation. Moreover, CD8+CD45RO+ memory T cells constitutively expressed TLR4 and markedly enhanced IFN‐γ production when stimulated with LPS. In contrast, activated murine CD8+ T cells lack TLR4 and CD14 expression and fail to respond to LPS for proliferation and cytokine production. Thus, human but not murine CD8+ T cells are able to directly recognise bacterial LPS via LPS receptor complex and TLR4 provides a novel signal for the activation of effector and memory human CD8+ T cells. 相似文献
17.
HBV‐specific CD4+ cytotoxic T cells in hepatocellular carcinoma are less cytolytic toward tumor cells and suppress CD8+ T cell‐mediated antitumor immunity
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Fanzhi Meng Shoumei Zhen Bin Song 《APMIS : acta pathologica, microbiologica, et immunologica Scandinavica》2017,125(8):743-751
In East Asia and sub‐Saharan Africa, chronic infection is the main cause of the development of hepatocellular carcinoma, an aggressive cancer with low survival rate. Cytotoxic T cell‐based immunotherapy is a promising treatment strategy. Here, we investigated the possibility of using HBV‐specific CD4+ cytotoxic T cells to eliminate tumor cells. The naturally occurring HBV‐specific cytotoxic CD4+ and CD8+ T cells were identified by HBV peptide pool stimulation. We found that in HBV‐induced hepatocellular carcinoma patients, the HBV‐specific cytotoxic CD4+ T cells and cytotoxic CD8+ T cells were present at similar numbers. But compared to the CD8+ cytotoxic T cells, the CD4+ cytotoxic T cells secreted less cytolytic factors granzyme A (GzmA) and granzyme B (GzmB), and were less effective at eliminating tumor cells. In addition, despite being able to secrete cytolytic factors, CD4+ T cells suppressed the cytotoxicity mediated by CD8+ T cells, even when CD4+CD25+ regulator T cells were absent. Interestingly, we found that interleukin 10 (IL‐10)‐secreting Tr1 cells were enriched in the cytotoxic CD4+ T cells. Neutralization of IL‐10 abrogated the suppression of CD8+ T cells by CD4+CD25? T cells. Neither the frequency nor the absolute number of HBV‐specific CD4+ cytotoxic T cells were correlated with the clinical outcome of advanced stage hepatocellular carcinoma patients. Together, this study demonstrated that in HBV‐related hepatocellular carcinoma, CD4+ T cell‐mediated cytotoxicity was present naturally in the host and had the potential to exert antitumor immunity, but its capacity was limited and was associated with immunoregulatory properties. 相似文献
18.
The Ex Vivo Induction of Human CD103+ CD25hi Foxp3+ CD4+ and CD8+ Tregs is IL‐2 and TGF‐β1 Dependent
B. Gunnlaugsdottir S. M. Maggadottir I. Skaftadottir B. R. Ludviksson 《Scandinavian journal of immunology》2013,77(2):125-134
The expression of the integrin αE (CD103), may enhance the retention of regulatory T cells to peripheral inflammatory sites and possibly contribute to their suppressive potential. The aim of this study was to define the regulatory role of IL‐2 and TGF‐β1 on the CD103 expression and the optimal in vitro conditions for the induction/expansion of human CD4+ and CD8+ Tregs. Cord blood mononuclear cells (CBMC) were stimulated under various culture conditions, including anti‐CD3, anti‐CD28, IL‐2 and TGF‐β1. TGF‐β1 and IL‐2 were both required for optimal expression of CD103. In addition, TGF‐β1 and IL‐2 synergistically induced CD103 expression on CD8+ T cells, whereas, only additive induced expression was noted on CD4+ T cells. Surprisingly, CD103 expression was not dependent upon CD28 costimulation. IL‐2 also played a central role in CD103 expression by CD25hi Foxp3+ Tregs. IL‐2, TGF‐β1 and anti‐CD3 defined the optimal stimulatory conditions favouring the induction/expansion of both CD4+ and CD8+ human Tregs from naive CBMC. Thus, this study provides new insights into the regulatory role of IL‐2 upon CD103 expression by human cord blood CD4+ and CD8+ T cells. Furthermore, it identifies the in vitro culture conditions driving the differentiation of the novel phenotype CD4+ and CD8+ CD103+ CD25hi Foxp3+ Tregs from human CBMC. 相似文献
19.
Phosphorylated STAT3 and PD‐1 regulate IL‐17 production and IL‐23 receptor expression in Mycobacterium tuberculosis infection
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Anuradha Bandaru Kamakshi P. Devalraju Padmaja Paidipally Rohan Dhiman Sambasivan Venkatasubramanian Peter F. Barnes Ramakrishna Vankayalapati Vijayalakshmi Valluri 《European journal of immunology》2014,44(7):2013-2024
We studied the factors that regulate IL‐23 receptor expression and IL‐17 production in human tuberculosis infection. Mycobacterium tuberculosis (M. tb)‐stimulated CD4+ T cells from tuberculosis patients secreted less IL‐17 than did CD4+ T cells from healthy tuberculin reactors (PPD+). M. tb‐cultured monocytes from tuberculosis patients and PPD+ donors expressed equal amounts of IL‐23p19 mRNA and protein, suggesting that reduced IL‐23 production is not responsible for decreased IL‐17 production by tuberculosis patients. Freshly isolated and M. tb‐stimulated CD4+ T cells from tuberculosis patients had reduced IL‐23 receptor and phosphorylated STAT3 (pSTAT3) expression, compared with cells from PPD+ donors. STAT3 siRNA reduced IL‐23 receptor expression and IL‐17 production by CD4+ T cells from PPD+ donors. Tuberculosis patients had increased numbers of PD‐1+ T cells compared with healthy PPD+ individuals. Anti‐PD‐1 antibody enhanced pSTAT3 and IL‐23R expression and IL‐17 production by M. tb‐cultured CD4+ T cells of tuberculosis patients. Anti‐tuberculosis therapy decreased PD‐1 expression, increased IL‐17 and IFN‐γ production and pSTAT3 and IL‐23R expression. These findings demonstrate that increased PD‐1 expression and decreased pSTAT3 expression reduce IL‐23 receptor expression and IL‐17 production by CD4+ T cells of tuberculosis patients. 相似文献
20.
Atsushi Fukui Evangelos Ntrivalas Rie Fukuhara Shunsaku Fujii Hideki Mizunuma Alice Gilman-Sachs Kenneth Beaman Joanne Kwak-Kim 《American journal of reproductive immunology (New York, N.Y. : 1989)》2009,62(6):371-380
Problem Natural cytotoxicity receptors (NCRs) are unique markers, which regulate NK cell cytotoxicity and cytokine production. We investigated whether women with recurrent pregnancy losses (RPLs) and implantation failures have aberrant correlation between NCRs and intracellular cytokine expression of NK cells. Method of study Peripheral blood NK cells (CD56dim and CD56bright) were analyzed for NCRs (NKp46, NKp44 and NKp30) and cytokine expression (TNF‐α, IFN‐γ, IL‐4, IL‐10) using flow cytometry in RPL (n = 22), implantation failures (n = 23) or controls (n = 15). Results In type 1 cytokine studies, CD56bright/NKp30+ cells in controls (r = 0.696, P < 0.05) were positively correlated with CD56bright/IFN‐γ+/TNF‐α+ cells. CD56bright/NKp46+ cells in implantation failures (r = ?0.76, P < 0.01) were negatively correlated with CD56bright/IFN‐γ+/TNF‐α? cells. RPL did not have any correlation. In type 2 cytokine studies, CD56+/NKp46+ cells (r = 0.758, P < 0.01) and CD56+/NKp30+ cells (r = 0.637, P < 0.05) were positively correlated with CD56bright/IL‐4+/IL‐10+ cells in controls. CD56+/NKp30+ cells in implantation failures (r = ?0.778, P < 0.05) were negatively correlated with CD56bright/IL‐10+/IL‐4+ cells. There were no correlations in RPL. Conclusion Recurrent pregnancy losses and implantation failures have lack of, or negative correlation between NCRs and intracellular cytokines expression. This observation suggests that excessive pro‐inflammatory cytokine expression in NK cells in RPL and implantation failures may be exerted through the NCRs or interruption of signal transduction processes. 相似文献